Gene regulation by steroids is mediated by the binding of the endogenous or pharmacological ligand to the corresponding nuclear receptor. Ligand-activated steroid receptors usually regulate the expression of responsive genes by binding to common response elements on DNA as homodimers. However, recent findings indicate that mineralocorticoid and glucocorticoid receptors are able to interact by forming heterodimers. In tissues coexpressing both of these corticosteroid receptors, heterodimerization between them may be a hitherto unrecognized modality for the transcriptional regulation of corticosteroid-responsive genes. In this review, Thorsten Trapp and Florian Holsboer discuss the potential impact of this heterodimerization on corticosteriod physiology and pharmacology.